The antimetabolite drug hydroxyurea (HU) has been used to treat a variety of human cancers including chronic myelogenous leukemia, head and neck cancer, and others (1). Its primary anticancer target is ribonucleotide reductase (RR), which reduces ribonucleotides to their corresponding deoxy forms to supply dNTPs for DNA replication and repair (3,4). The human RR is composed of the hRRM1 and hRRM2 subunits (3,4). Following a genotoxic stimulus, an alternate RR enzyme is induced to supply dNTPs for DNA repair, which is composed of hRRM1 and p53R2 (a homologue of hRRM2 transactivated by the tumor suppressor protein p53) (5). Within cells, HU is known to inhibit both types of RR(4) through generating free radicals via oxidative transformation (6) that quenches free-radical mediated catalysis (3). However, pharmacologically, HU therapy suffers from short half-life in vivo and problematic side effects, most notably myelosuppression, and gastrointestinal and dermatologic effects (7).
Poly(ADP-ribose) polymerase-1 (PARP1) and PARP2 are both ADP-ribosyl transferases (ART) with roles in tumor development. ART members with PARP activity such as PARP1 contain a conserved catalytic domain with a highly conserved active site sequence (12-14). Following single strand DNA breaks PARP1 synthesizes ADP-ribose polymers from β-NAD+ substrate and transfers these to glutamate, lysine or aspartate residues of acceptor proteins (itself or other proteins), which are subsequently degraded by poly(ADP-ribose) glycohydrolase (PARG). During single strand DNA break repair (SSBR) or base-excision repair (BER), PARP1 and PARP2 interact with X-ray repair complementing protein-1 (XRCC 1) to recruit SSBR/BER factors, DNA polymerase β or DNA ligase III to the site of DNA damage (12-14). Without PARP1, the continuing presence of single strand breaks during DNA replication will lead to stalled replication forks, whose resolution require BRCA1 or BRCA2-mediated homologous repair (HR) (15,16). BRCA1 along with BRCA2 are tumor suppressor genes linked to the onset of familial breast cancers (11). In the absence of BRCA1, double strand breaks consequently accumulate, resulting in cell death via apoptosis. BRCA1/2-defective tumors may be sensitive to PARP1 inhibitors but can suffer from acquired resistance to PARP1 inhibitors. Thus, there is a need in the art for BRCA1/2-defective tumor treatments that avoid side effects and/or acquired resistance associated with current therapies. Accordingly, provided herein are solutions to these and other problems in the art.